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=Hypoxanthine-guanine phosphoribosyltransferase=

=Introduction= Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a key enzyme in purine salvage pathways. This enzyme salvages guanine directly and adenine indirectly from catabolism. It catalyzes the reversible transfer of the phosphoribosyl group from a-D-5-phosphoribosyl 1-pyrophosphate (PRPP) to hypoxanthine or guanine forming either IMP or GMP, respectively. This reaction is dependent on a divalent magnesium cation. HGPRT is deficient in Lesch-Nyhan syndrome, a severe neurological disorder characterized by high levels of blood uric acid and uncontrollable self mutilation. A partial deficiency of the enzyme leads to gouty arthritis.

=Structure= HGPRT belongs to a group of enzymes known as phosphoribosyltransferases (PRTases), which are involved in purine, pyrimidine and amino acid synthesis. HGPRT is a tetramer, which is required for enzyme function, since three of the four subunits contribute residues to each active site. The structures of PRTases fall into two groups, type 1 and type 2; HGPRT falls into the type 1 category. A common alpha/beta-fold called the PRPP motif and a flexible loop are structural characteristics of type 1 PRTases. Type 1 PRTases also have a core region containing at least five or more parallel beta strands surrounded by three or four helices. Type 2 PRTases do not have a PRPP motif and are composed of a alpha/beta N terminal domain and a alpha/beta barrel-like C terminal doimain. The characteristic loop of type 1 PRTases closes after substrate binding and is thought to sequester the active site from solvent during catalysis. In the crystal structure of the human HGPRT-GMP complex, the loop is open and the active site is exposed to the solvent. The PRTase from the parasite, Toxoplasma gondii, has a mobile loop that partially covers the active site, whereas the flexible loop in Trypanosoma cruzii does not sequester the second active site from solvent. =Function= Hypoxanthine-guanine phosphoribosyltransferase is present in many human tissues with the most specific activities occurring in the brain, placenta, gonads, erythrocytes, fibroblasts, and leukocytes. It's role is the conservation of purine bases that might otherwise be degraded to uric acid.

=Mechanism=  A base, either hypoxanthine or guanine, reacts with PRPP to form nucleoside monophosphate and pyrophosphate. The reaction, catalyzed by HGPRT, is reversible with rapid phosphoribosyl transfer in both the forward and reverse directions. In the forward direction PRPP binding occurs before GMP or IMP binding. Pyrophosphate then rapidly dissociates after the transition state followed by the release of the nucleoside monophosphate. In the reverse direction GMP or IMP binding precedes PRPP binding. The base then rapidly dissociates, whereas PRPP dissociates slowly. The acidic residues corresponding to Glu 133 and Asp 134 stabilize the oxocarbenium ion at the transition state. =Additional Resources= For additional information on PRTases, see: Sandbox Reserved 342

=References=